lithium-chloride and Hypoglycemia

Hypoglycemia is the most common complication in the treatment of diabetes mellitus. Accumulating evidence indicated that severe hypoglycemia could induce cognitive impairment. However, the molecular mechanism of regulating this progress is largely unknown.. We established a model of insulin-induced recurrent hypoglycemia in adult male Wistar rats (n = 40). Lithium chloride was injected after hypoglycemia once a day for consecutive 30 days. The loss of cognition function was evaluated by water maze test in these hypoglycemic rats. Glial cells activation and Wnt and inflammatory cytokines IL-1β, IL-6, IL-4, IL-10, TGFβ and TNFα expression were further examined to determine the mechanism of cognitive function impairment.. Hypoglycemia could induce impairment of cognitive function in rats and administration of lithium chloride could partly attenuate cognitive impairment compared to the control (p < 0.05). Lithium chloride could significantly up-regulate Wnt signaling and reduce hypoglycemia-induced neuronal death, glial cells activation and inflammatory response in the hippocampus of rats compared to the control (p < 0.05). The efficacy of lithium chloride could be reversed by injecting canonical Wnt signaling antagonist the dickkopf homolog 1.. Lithium chloride attenuated hypoglycemia-induced cognitive function impairment in rats; and it was associated with Wnt signaling up-regulation and reduction of inflammatory response. Our results suggested that activating Wnt signaling pathways and inhibiting inflammatory response were the therapeutic potential to prevent hypoglycemia-induced neurological damage.

Topics: Animals; Cell Death; Cognition; Cognitive Dysfunction; Hippocampus; Hypoglycemia; Hypoglycemic Agents; Insulin; Lithium Chloride; Male; Maze Learning; Neurons; Rats; Rats, Wistar; Signal Transduction

Hypoglycemia is defined by an arbitrary plasma glucose level lower than 3.9mmol/L and is a most common and feared adverse effect of treatment of diabetes mellitus. Emerging evidences demonstrated that hypoglycemia could induce enhanced apoptosis. Lithium chloride (LiCl), a FDA approved drug clinically used for treatment of bipolar disorders, is recently proven having neuroprotection against various stresses in the cellular and animal models of neural disorders. Here, we have established a hypoglycemia model in vitro and assessed the neuroprotective efficacy of LiCl against hypoglycemia-induced apoptosis and the underlying cellular and molecular mechanisms. Our studies showed that LiCl protects against hypoglycemia-induced neurotoxicity in vitro. Exposure to hypoglycemia results in enhanced apoptosis and the underlying cellular and molecular mechanisms involved inhibition of the canonical Wnt signaling pathway by decreasing wnt3a levels, β-catenin levels and increasing GSK-3β levels, which was confirmed by the use of Wnt-specific activator LiCl. Hypoglycemia-induced apoptosis were significantly reversed by LiCl, leading to increased cell survival. LiCl also alters the expression/levels of the Wnt pathway genes/proteins, which were reduced due to exposed to hypoglycemia. Overall, our results conclude that LiCl provides neuroprotection against hypoglycemia-induced apoptosis via activation of the canonical Wnt signaling pathway.

Topics: Animals; Apoptosis; Blotting, Western; Caspase 3; Cell Survival; Drug Evaluation, Preclinical; Flow Cytometry; Gene Expression; Hypoglycemia; Lactate Dehydrogenases; Lithium Chloride; Neuroprotective Agents; PC12 Cells; Rats; Real-Time Polymerase Chain Reaction; Wnt Signaling Pathway

Glucose transporter type 1 (Glut-1) facilitates glucose flux across the blood-brain-barrier. In humans, Glut-1 deficiency causes acquired microcephaly, seizures and ataxia, which are recapitulated in our Glut-1 haploinsufficient mouse model. Postnatal brain weight deceleration and development of reactive astrogliosis were significant by P21 in Glut-1(+/-) mice. The brain weight differences remained constant after P21 whereas the reactive astrocytosis continued to increase and peaked at P90. Brain immunoblots showed increased phospho-mTOR and decreased phospho-GSK3-beta by P14. After fasting, the mature Glut-1(+/-) females showed a trend towards elevated phospho-GSK3-beta, a possible neuroprotective response. Lithium chloride treatment of human skin fibroblasts from control and Glut-1 DS patients produced a 45% increase in glucose uptake. Brain imaging of mature Glut-1(+/-) mice revealed a significantly decreased hippocampal volume. These subtle immunochemical changes reflect chronic nutrient deficiency during brain development and represent the experimental correlates to the human neurological phenotype associated with Glut-1 DS.

Topics: Age Factors; Animals; Animals, Newborn; Apoptosis; Astrocytes; Body Weight; Brain; Carbohydrate Metabolism, Inborn Errors; Carrier Proteins; Cell Proliferation; Cell Size; Cells, Cultured; Dendrites; Disease Models, Animal; Female; Fibroblasts; Gene Expression Regulation, Developmental; Glial Fibrillary Acidic Protein; Gliosis; Glucose Transporter Type 1; Humans; Hypoglycemia; In Situ Nick-End Labeling; Lithium Chloride; Magnetic Resonance Imaging; Male; Mice; Mice, Knockout; Neurons; Organ Size; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Skin; TOR Serine-Threonine Kinases